title: Enhanced and sustained topical ocular delivery of cyclosporine A in thermosensitive hyaluronic acid-based in situ forming microgels.
abstract: For nearly a decade, thermoresponsive ophthalmic in situ gels have been recognized as an interesting and promising ocular topical delivery vehicle for lipophilic drugs. In this study, a series of thermosensitive copolymers, hyaluronic acid-g-poly(N-isopropylacrylamide) (HA-g-PNIPAAm), was synthesized, by coupling carboxylic end-capped PNIPAAm to aminated hyaluronic acid through amide bond linkages, and was used as a potential carrier for the topical ocular administration of cyclosporine A (CyA). The lower critical solution temperature of HA-g-PNIPAAm59 in aqueous solutions was measured as 32.7°C, which was not significantly affected by the polymer concentration. Moreover, HA-g-PNIPAAm59 microgels showed a high drug loading efficiency (73.92%) and a controlled release profile that are necessary for biomedical application. Transmission electron microscopy (TEM) and atomic force microscopy (AFM) observations showed that HA-g-PNIPAAm microgels were spherical in shape with homogeneous size. Based on the result of the eye irritation test, the HA-g-PNIPAAm microgels formulation was shown to be safe and nonirritant for rabbit eyes. In addition, HA-g-PNIPAAm microgels achieved significantly higher CyA concentration levels in rabbit corneas (1455.8 ng/g of tissue) than both castor oil formulation and commercial CyA eye drops. Therefore, these newly described thermoresponsive HA-g-PNIPAAm microgels demonstrated attractive properties to serve as pharmaceutical delivery vehicles for a variety of ophthalmic applications.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang, Nanjing, People's Republic of China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Wu
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.forename: Fatima Zohra
authors.initials: FZ
authors.lastname: Dahmani
mesh_terms: D060433:Administration, Ophthalmic; D000818:Animals; D002214:Capsules / Q000009:adverse effects / Q000138:chemical synthesis*; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects* / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects* / Q000138:chemical synthesis*; D009877:Endophthalmitis / Q000139:chemically induced* / Q000473:pathology; D005782:Gels / Q000737:chemistry; D006820:Hyaluronic Acid / Q000009:adverse effects / Q000737:chemistry*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D011817:Rabbits; D013696:Temperature
chemical_list: D002214:Capsules; D003692:Delayed-Action Preparations; D005782:Gels; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D006820:Hyaluronic Acid
keywords: cyclosporine A; hyaluronic acid; ophthalmic drug delivery; thermosensitive microgels